Fish oil targets PTEN to regulate NFkappaB for downregulation of anti-apoptotic genes in breast tumor growth.
The molecular mechanism for the beneficial effect of fish oil on breast tumor growth is largely undefined. Using the xenograft model in nude mice, we for the first time report that the fish oil diet significantly increased the level of PTEN protein in the breast tumors. In addition, the fish oil diet attenuated the PI 3 kinase and Akt kinase activity in the tumors leading to significant inhibition of NFkappaB activation. Fish oil diet also prevented the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL in the breast tumors with concomitant increase in caspase 3 activity. To extend these findings we tested the functional effects of DHA and EPA, the two active omega-3 fatty acids of fish oil, on cultured MDA MB-231 cells. In agreement with our in vivo data, DHA and EPA treatment increased PTEN mRNA and protein expression and inhibited the phosphorylation of p65 subunit of NFkappaB in MDA MB-231 cells. Furthermore, DHA and EPA reduced expression of Bcl-2 and Bcl-XL. NFkappaB DNA binding activity and NFkappaB-dependent transcription of Bcl-2 and Bcl-XL genes were also prevented by DHA and EPA treatment. Finally, we showed that PTEN expression significantly inhibited NFkappaB-dependent transcription of Bcl-2 and Bcl-XL genes. Taken together, our data reveals a novel signaling pathway linking the fish oil diet to increased PTEN expression that attenuates the growth promoting signals and augments the apoptotic signals, resulting in breast tumor regression.
Ghosh-Choudhury
Triparna
T
Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Mandal
Chandi C
CC
Woodruff
Kathleen
K
St Clair
Patricia
P
Fernandes
Gabriel
G
Choudhury
Goutam G
GG
Ghosh-Choudhury
Nandini
N
D000230:Adenocarcinoma / Q000178:diet therapy / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000178:diet therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
C494811:BCL2L1 protein, human; D004273:DNA, Neoplasm; D005395:Fish Oils; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C498143:RELA protein, human; D051996:Transcription Factor RelA; D051020:bcl-X Protein; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human